Thymidine phosphorylase expression causes both the increase of intratumoral microvessels and decrease of apoptosis in human esophageal carcinomas

Okamoto, Eiji; Osaki, Mitsuhiko; Kase, Satoru; Adachi, Hisashi; Kaibara, Nobuaki; Ito, Hisao

doi:10.1046/j.1440-1827.2001.01184.x

Cited by 23 publications

(29 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The enzymatic activity of TP and its catalytic products, 2-deoxy-D-ribose (2-DDR)-1-phosphate and downstream 2-DDR, can induce angiogenesis in vivo and in vitro [19] . Moreover, TP expression was found to inhibit apoptosis of tumor cells, which might occur via a p53 gene-independent pathway [20] . Therefore, TP may play an important role in tumor growth of RCC through TP-induced angiogenic activity and prevention of apoptosis by TP.…”

Section: Discussionmentioning

confidence: 99%

Poor Prognosis Associated with High Levels of Thymidine Phosphorylase and Thrombocytosis in Patients with Renal Cell Carcinoma

Huang

Wang²,

Chen³

et al. 2016

Urol Int

View full text Add to dashboard Cite

Purpose: The study aimed to investigate the expression of thymidine phosphorylase (TP) in renal cell carcinoma (RCC) and its correlation with clinicopathological features and thrombocytosis, and also to determine their prognostic significance. Patients and Methods: TP expression in 127 RCC specimens was evaluated with immunohistochemistry assays. Platelet (PLT) counts of patients before surgery were recorded. Correlations among TP expression, PLT and the clinicopathological features of the patients and their prognostic values were studied statistically. Results: Sixty-eight patients of high TP expression (54%) and 59 of low TP expression (46%) were detected. There were 25 patients with thrombocytosis (20%). High TP expression was significantly associated with tumor stage (p = 0.004), histological grade (p = 0.001) and thrombocytosis (p = 0.012). The 5-year overall survival rate was 88.1% in patients with low TP expression, whereas it was 61.8% in patients with high TP expression (p < 0.001). The 5-year survival rates for patients with and without thrombocytosis were 16.0% and 88.2%, respectively (p < 0.001). The multivariate analysis showed that high TP expression and thrombocytosis would play a role as independent prognostic factors in RCC patients. Conclusion: High TP expression and thrombocytosis can be regarded as independent prognostic factors of poor survival in patients with RCC.

show abstract

Section: Discussionmentioning

confidence: 99%

Poor Prognosis Associated with High Levels of Thymidine Phosphorylase and Thrombocytosis in Patients with Renal Cell Carcinoma

Huang

Wang²,

Chen³

et al. 2016

Urol Int

View full text Add to dashboard Cite

show abstract

“…Moreover, TPase levels correlate well with microvessel density in breast, ovarian, colorectal, endometrial, and esophageal cancers (8 -12), pointing to an important role for this enzyme in tumor vascularization. In addition, TPase has been shown to inhibit tumor cell apoptosis (12). Therefore, there is an anti-cancer potential for potent and specific TPase inhibitors.…”

mentioning

confidence: 99%

The Nucleoside Derivative 5′-O-Trityl-inosine (KIN59) Suppresses Thymidine Phosphorylase-triggered Angiogenesis via a Noncompetitive Mechanism of Action

Liekens

Hernández

Ribatti

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Thymidine phosphorylase (TPase) catalyzes the reversible phosphorolysis of pyrimidine deoxynucleosides to 2-deoxy-D-ribose-1-phosphate and their respective pyrimidine bases. The enzymatic activity of TPase was found to be essential for its angiogenesis-stimulating properties. All of the previously described TPase inhibitors are either pyrimidine analogues that interact with the nucleosidebinding site of the enzyme or modified purine derivatives that mimic the pyrimidine structure and either compete with thymidine or act as a multisubstrate (competitive) inhibitor. We now describe the inhibitory activity of the purine riboside derivative KIN59 (5 -O-tritylinosine) against human and bacterial recombinant TPase and TPase-induced angiogenesis. In contrast to previously described TPase inhibitors, KIN59 does not compete with the pyrimidine nucleoside or the phosphate-binding site of the enzyme but noncompetitively inhibits TPase when thymidine or phosphate is used as the variable substrate. In addition, KIN59 was far more active than other TPase inhibitors, previously tested by us, against TPase-induced angiogenesis in the chorioallantoic membrane assay. The observed anti-angiogenic effect of KIN59 was not accompanied by inflammation or any visible toxicity. Inosine did not inhibit the enzymatic or angiogenic activity of the enzyme, indicating that the 5 -O-trityl group in KIN59 is essential for the observed effects. In contrast with current concepts, our data indicate that the angiogenic activity of TPase is not solely directed through its functional nucleoside and phosphate-binding sites. Other regulatory (allosteric) site(s) in TPase may play an important role in the mechanism of TPase-triggered angiogenesis stimulation and apoptosis inhibition. Identification of these site(s) is important to obtain a better insight into the molecular role of TPase in the progression of cancer and angiogenic diseases.Angiogenesis is the process by which new blood vessels arise from pre-existing vessels (1). It is essential during embryogenesis for the formation of a vascular plexus, which ensures an adequate blood supply to all developing tissues. In adults, neovascularization is limited to wound healing and the female reproductive cycle. During these processes, angiogenesis is tightly regulated. Unregulated angiogenesis may lead to the progression of several inflammatory diseases and is an essential component of solid tumor growth and metastasis. The formation of new blood vessels requires several sequential steps, which are regulated by a number of angiogenic factors, including chemokines, growth factors, integrins, and enzymes, such as proteases and thymidine phosphorylase (TPase) 1 (1).TPase is an enzyme that catalyzes the reversible phosphorolysis of pyrimidine 2Ј-deoxynucleosides to 2-deoxyribose 1-phosphate and their respective pyrimidine bases. TPase also recognizes several nucleoside analogues that are being used clinically as antiviral

show abstract

“…Thymidine phosphorylase is a relevant target by being both an angiogenesis-promoting factor, and the intracellular activator of 5FU prodrugs. This enzyme is widely expressed in humans cancers (Zimmerman and Seidenberg, 1964), and higher levels of TP expression are associated with increased intratumoral microvessel density (MVD) and an unfavourable prognosis (Okamoto et al, 2001). Nuclear TP (TP-nuc) correlated with MVD, and was inversely related with response and outcome in HNSCC patients treated with 5FU, cisplatin and radiotherapy (Koukourakis et al, 2000).…”

mentioning

confidence: 99%

Phase II trial of cisplatin and capecitabine in patients with squamous cell carcinoma of the head and neck, and correlative study of angiogenic factors

et al. 2004

View full text Add to dashboard Cite

The combination of cisplatin and capecitabine was evaluated in patients with recurrent or unresectable squamous cell carcinoma of the head and neck (HNSCC), and outcome parameters were correlated with the expression of thymidine phosphorylase (TP), thymidilate syntetase (TS), vascular endothelial growth factor receptor (VEGFR) 1 -3, and microvessel density (MVD). Patients with recurrent or unresectable HNSCC were eligible if they had received prior neoadjuvant chemotherapy, concurrent chemoradiotherapy, or no prior systemic therapy. Patients received cisplatin (75 mg m À2 day 1), and capecitabine (2000 mg m À2 day 1 -14) every 3 weeks. A total of 41 patients received 194 cycles. In all, 16 complete responses (39%) and 12 partial responses (29%) were documented, for an overall response rate of 68% (95% CI, 53 -80%). Grade 3 -4 uncomplicated neutropenia was documented in five subjects. Asthenia, anorexia, hand -foot syndrome, and constipation were the most frequent nonhaematologic events. Median progression-free and overall survival were 6.4 and 12.6 months. Cytoplasmic TP expression was more prevalent in patients with a laryngeal location vs other, and in patients with a recurrence vs primary disease. Microvessel density count was higher in patients with recurrent vs primary disease. The combination of cisplatin and capecitabine is effective in recurrent or unresectable HNSCC, and shows a manageable toxicity.

show abstract

Thymidine phosphorylase expression causes both the increase of intratumoral microvessels and decrease of apoptosis in human esophageal carcinomas

Cited by 23 publications

References 37 publications

Poor Prognosis Associated with High Levels of Thymidine Phosphorylase and Thrombocytosis in Patients with Renal Cell Carcinoma

Poor Prognosis Associated with High Levels of Thymidine Phosphorylase and Thrombocytosis in Patients with Renal Cell Carcinoma

The Nucleoside Derivative 5′-O-Trityl-inosine (KIN59) Suppresses Thymidine Phosphorylase-triggered Angiogenesis via a Noncompetitive Mechanism of Action

Phase II trial of cisplatin and capecitabine in patients with squamous cell carcinoma of the head and neck, and correlative study of angiogenic factors

Contact Info

Product

Resources

About